Although oxygen is required to sustain life, the physical characteristics of oxygen also make it potentially harmful to life. For example, oxygen toxicity can occur when 100% oxygen is inspired at normal atmospheric pressure (Jackson, R. M., Chest, 86(6):900-905 (1985)) or when breathing molecular oxygen (O2) at elevated partial pressures (Allen, B. W., et al., J. Appl Physiol, 106:662-667 (2009)). Individuals at risk for developing pulmonary oxygen toxicity include scuba divers, individuals on high concentrations of supplemental oxygen (particularly premature infants), and those undergoing hyperbaric oxygen therapy.
Oxygen toxicity occurs when higher than typical physiological concentrations of oxygen lead to increased levels of reactive oxygen species (ROS). Oxygen can be reduced in the body by one or two electrons to form ROS which are natural by-products of the normal metabolism of oxygen and have important roles in cell signaling. When oxygen is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most vascularized tissues being most vulnerable. During times of environmental stress, levels of ROS can increase dramatically, which can damage cell structures and produce oxidative stress.
One of the most reactive ROS products of oxidative stress is the hydroxyl radical (OH), which can initiate a damaging chain reaction of lipid peroxidation in the unsaturated lipids within cell membranes. High concentrations of oxygen also increase the formation of other ROS free radicals, such as nitric oxide (NO), superoxide anion (.O2−), perhydroxy radical (HOO.), peroxynitrite, and trioxidane, which harm DNA and other biomolecules. Although the body has many antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the capacity of the systems that prevent or repair it. (Allen, B. W., et al., J. Appl Physiol, 106:662-667 (2009)). Cell damage and cell death can then result.
Increased generation of ROS can occur as a result of many conditions affecting newborn infants including hyperoxia, reperfusion, or inflammation. Supplemental oxygen in premature infants contributes to the development of chronic lung disease (bronchopulmonary dysplasia (BPD)), characterized by dysregulated inflammation and altered expression of proteases and growth factors (Davis, et al., Seminars in Fetal & Neonatal Medicine, 15:191-195 (2010)). More specifically, the high pressures of oxygen delivery result in necrotizing bronchiolitis and alveolar septal injury, further compromising oxygenation of blood.
Hyperoxia may also be a contributing factor for the disorder called retrolental fibroplasia or retinopathy of prematurity (ROP) in infants. In preterm infants, the retina is often not fully vascularised. Retinopathy of prematurity occurs when the development of the retinal vasculature is arrested and then proceeds abnormally. Associated with the growth of these new vessels is fibrous tissue (scar tissue) that may contract to cause retinal detachment.
Currently, the preferred way to manage oxygen toxicity is to monitor the amount of oxygen delivered to the subject. Other therapies include the administration of antioxidants, enzymes that help produce antioxidants, or compounds that stimulate the production of antioxidants to a subject. These additional therapies have had limited success.
Despite the possible toxic effects of oxygen therapy, the need for supplemental oxygen therapy remains.
It is therefore an object of the invention to provide compositions and methods for inhibiting, reducing, or preventing oxygen toxicity in a subject.
It is another object of the invention to provide compositions and methods for inhibiting or reducing pulmonary oxygen toxicity.